Summary
A novel immunotherapy is showing long-term promise for the treatment of unresectable stage IIIB or stage IV melanoma in the form of a genetically modified herpes virus. Talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic virus therapy, provided a 12-month progression-free survival (PFS) of 14.4 percent—a significant improvement from the 4.6 percent experienced by those treated with granulocyte-macrophage colony-stimulating factor (GM-CSF).
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Original Article
Modified Herpes Virus Increases Survival in Advanced Melanoma
Oncology Times
By Rebecca Hepp
A novel immunotherapy is showing long-term promise for the treatment of unresectable stage IIIB or stage IV melanoma in the form of a genetically modified herpes virus. Talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic virus therapy, provided a 12-month progression-free survival (PFS) of 14.4 percent—a significant improvement from the 4.6 percent experienced by those treated with granulocyte-macrophage colony-stimulating factor (GM-CSF).
Modification
T-VEC is created by genetically modifying the herpes simplex virus, type 1 (Am J Clin Dermatol 2017; doi: 10.1007/s40257-016-0238-9). Researchers delete the herpes neurovirulence genes to decrease its pathogenicity and delete the viral ICP47 gene to improve the therapy’s immunogenicity. The resulting treatment capitalizes on the beneficial traits of the herpes virus, including its ability to preferentially infect and replicate in tumor cells, triggering tumor cell death and boosting the patient’s anti-tumor immunity.
Back in 2009 when Igor Puzanov, MD, Director of the Early Phase Clinical Trials Program and Chief of Melanoma at Roswell Park Comprehensive Cancer Center, became involved in the research, T-VEC was an obscure, niche therapy—one many doctors weren’t sure would pan out.
“But to me it had a lot of positive features,” Puzanov explained. “This was a modified virus injected into the melanoma tumors, and we have known for a long time that injecting melanoma with immunotherapy may be beneficial.” Additionally, William B. Coley was injecting cancer tumors with streptococcal organisms in the 1800s, with close to a 30 percent response rate, Puzanov noted (Iowa Orthop J 2006;26:154-158).
“The idea is that, if you infect a tumor, the body will clear the infection, and as the body is clearing the infection, it may see the cancer as foreign and clear the cancer as well,” he described. And so far, this first-in-class oncolytic virus therapy seems to be doing just that.
Although the therapy is limited to local treatment for certain melanoma patients, the efficacy can often manifest systemically, according to Puzanov. “Once you train the immune system locally, it’s very similar to when you get a vaccine. The shot is local, in the arm, but then the whole body is protected from the virus.” In the same way, T-VEC produces GM-CSF, leading to T-cell activation. Those T cells proliferate and migrate to distant metastases—triggering antitumor activity.
“It has been very fulfilling because there were a lot of skeptics of the project,” Puzanov added. “Whatever we said about the drug initially, it seems to be confirmed that it works in many patients.”
Study Details
Puzanov’s recent phase III study compared the novel oncolytic virus therapy with a standard GM-CSF regimen in 436 patients with unresectable stage IIIB or IV melanoma. Previous research already shows an improved durable response rate in patients treated with T-VEC compared with GM-CSF, 16.3 percent vs. 2.1 percent.
This time, Puzanov and his team were looking at PFS in the intention-to-treat population, 57 percent of whom were diagnosed with stage IIIB-IVM1a, and the other 43 percent had stage IVM1b-IVM1c. The median age was 63, and 57 percent were men.
Patients were randomized to either intralesional T-VEC (68%) or subcutaneous GM-CSF (32%). Overall, those who received T-VEC experienced significantly improved PFS, although the stage of the disease was an important factor.
Patients with stage IIIB-IVM1a melanoma in the T-VEC treatment group experienced particularly improved PFS (19.9%) compared with similarly staged patients on GM-CSF (3.2%). The researchers observed no difference in PFS between treatment groups for stage IVM1b-IVM1c (7.4% for the T-VEC arm vs. 8.0% for the GM-CSF arm).
Importantly, “we haven’t seen any increase in toxicity,” Puzanov explained. “When you look at progression-free survival and the response rate, it seems to be holding, especially with stage IIIB, IIIC and IVA.”
Treatment in Practice
Since T-VEC’s approval in 2015, it has become an important treatment option for patients with advanced melanoma. But it’s not a therapy just anyone can administer, according to Puzanov. Unlike oral or IV medications, T-VEC is intralesional, and a modified virus to boot. Anyone treating patients with it must abide by specific practice rules and have processes in place to handle the virus—and its disposal—properly. Puzanov suggests practitioners only seeing one or two patients a year refer them to a local expert that already has the logistics worked out. For those who want to start using T-VEC in their practice, Puzanov and his team at Roswell are always happy to consult.
“You always want to treat patients were they live when you can, and this is an FDA standard-of-care therapy,” Puzanov noted. “But learning how to do one treatment might not be worth your time, and that’s when you should reach out to the specialists.”
Next Frontiers
As promising as these findings are, Puzanov is already forging ahead with research into combination treatments to find the best responses possible. Published data already shows T-VEC paired with the global checkpoint inhibitor ipilimumab provides responses in distant metastases, he said. The combination provided an objective response rate of 39 percent compared with 18 percent for the ipilimumab-only group (J Clin Oncol 2017; doi:10.1200/JCO.2017.73.7379).
T-VEC with a second global checkpoint inhibitor, pembrolizumab, is another promising combination. “We have to wait and see because those results are not mature yet,” Puzanov cautioned, but “the early indications are that this drug may make a big difference in patients’ lives with relatively similar side effects as are seen with either drug alone.”
While these combinations all treat advanced melanoma, T-VEC may help patients far sooner than that, according to Puzanov.
“An interesting area of research is using T-VEC as a neoadjuvant treatment in earlier stages of melanoma, stage II for example, where they inject the tumor before excision, which might improve survival,” Puzanov explained.
Survival rates in early stage melanoma are decent, maybe even 90 percent, he added, but “those 10 percent are still a significant number, and it’s worth trying to save as many as possible.” And neoadjuvant T-VEC might be an easy answer.
“If that shows improved survival for stage I or stage II melanoma, maybe by 50 percent, that would be similar to the results we have for breast cancer patients,” according to Puzanov. Studies are needed to explore the possibility, “but if we can treat earlier stages with T-VEC and prevent cancer from spreading, we can save more patients from the start.”
Rebecca Hepp is a contributing writer.